Small Molecule Screening for Longevity Effects in Nematode Worms

A very large fraction of the research aimed at the production of interventions to slow aging involves some form of screening small molecule compounds for potential effects. There are huge stock libraries of these things, and many well established approaches to carrying out such screening processes. While new ventures are using machine learning to try to make this process far more efficient than is presently the case, after the fashion of In Silico Medicine, I'd say that the future will be a matter of gene therapy making small molecules obsolete. Gene therapy offers the possibility of precise alteration of the gene expression of a rationally chosen target, rather than the uncertainty, serendipity, and off-target effects inherent in small molecule development.

Still, much of the community, particularly the business community, will remain firmly tied to small molecule development programs for the foreseeable future. Researchers will continue to innovate when it comes to novel ways to run such programs. The example here makes use of nematode worms as the screening system: pick a set of compounds, see what they do to worm longevity, then investigate the biochemistry of the successes to understand whether or not they work in the expected fashion, and whether or not the mechanism might be applicable to mammals.

It is worth noting that most such discoveries work via alterations of stress response systems or other aspects of metabolism that do not produce large gains in life span in long-lived species. A doubling or more of nematode life span has been achieved in a variety of ways, but none of those are based on underlying mechanisms that have anywhere near the same effects when triggered in mammals. We need to look elsewhere to achieve that outcome, meaning work on deliberative repair of the underlying causes of aging, rather than adjustment of metabolism to modestly slow aging.

Discovery of life-extension pathway in worms demonstrates new way to study aging

Lifespan studies using C. elegans worms typically involve the deletion or silencing of a particular gene in the embryonic stage of life to see if that extends the average lifespan of affected animals. Researchers took a different approach, using small-molecule compounds to disrupt enzyme-related pathways in adult worms, in the hope that this would uncover pathways that regulate lifespan. The team used a library of about 100 such compounds, all known to inhibit enzymes called serine hydrolases in mammals. "Metabolic processes are very important in determining the rate of aging and lifespan, and serine hydrolases are major metabolic enzymes, so we thought there was a good chance we'd find an important aging-related enzyme this way."

After finding ways to get the compounds through the tough outer skin of the worms, the researchers tested them on worms that were 1 day into adulthood, and found that some of the compounds extended average worm lifespan by at least 15 percent. One, a carbamate compound called JZL184, extended worm lifespan by 45 percent at the optimal dose. More than half the worms treated with JZL184 were still alive and apparently healthy at 30 days, a time when virtually all untreated worms were dead of old age. JZL184 was originally developed as an inhibitor of the mammalian enzyme monoacylglycerol lipase (MAGL), whose normal job includes the breakdown of a molecule called 2-AG. The latter is an important neurotransmitter and is known as an endocannabinoid because it activates one of the receptors hit by the main psychoactive component in cannabis.

Curiously however, a corresponding MAGL enzyme does not exist in C. elegans worms, so JZL184's target in these animals was a mystery. Researchers found, though, that one of the main target enzymes for JZL184 in worms was fatty acid amide hydrolase 4 (FAAH-4). Although FAAH-4 and MAGL are not related in terms of their amino-acid sequences or 3-D folds, further experiments revealed, surprisingly, that FAAH-4 in worms does what MAGL does in humans and other mammals: it breaks down 2-AG. 2-AG has been linked to aging in mammals; one recent study found evidence that its levels fall in the brains of aging mice, likely due to greater MAGL activity. The results suggest, then, that studying the FAAH-4/2-AG pathway in worms could one day yield lifespan-extending strategies for humans.

Pharmacological convergence reveals a lipid pathway that regulates C. elegans lifespan

Phenotypic screening has identified small-molecule modulators of aging, but the mechanism of compound action often remains opaque due to the complexities of mapping protein targets in whole organisms. Here, we combine a library of covalent inhibitors with activity-based protein profiling to coordinately discover bioactive compounds and protein targets that extend lifespan in Caenorhabditis elegans. We identify JZL184 - an inhibitor of the mammalian endocannabinoid (eCB) hydrolase monoacylglycerol lipase (MAGL or MGLL) - as a potent inducer of longevity, a result that was initially perplexing as C. elegans does not possess an MAGL ortholog.

We instead identify FAAH-4 as a principal target of JZL184 and show that this enzyme, despite lacking homology with MAGL, performs the equivalent metabolic function of degrading eCB-related monoacylglycerides in C. elegans. Small-molecule phenotypic screening thus illuminates pure pharmacological connections marking convergent metabolic functions in distantly related organisms, implicating the FAAH-4/monoacylglyceride pathway as a regulator of lifespan in C. elegans.

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